Radiation therapy, a common treatment for malignancies, can cause severe damage to the lung—a highly radiosensitive organ. Radiation can cause a broad spectrum of pneumopathies, including acute-phase alveolitis/pneumonitis, late-stage chronic pulmonary fibrosis, and various respiratory dysfunctions such as dyspnea and pulmonary edema.
During the acute phase of radiation-induced lung injury, inflammation is the predominant histological and physiologic feature. The initial injury to lung tissues results in infiltration of inflammatory cells, such as macrophages and neutrophils; focal accumulation of mononuclear cells; increased levels of inflammatory cytokines such as transforming growth factor-β (TGF-β), interleukin-1α (IL-1α), and tumor necrosis factor (TNFα); and a decline in pulmonary function.
Radiation also induces late-stage pulmonary fibrosis—an insidious fibroproliferative condition characterized by a gradual, irreversible replacement of normal parenchyma cells with fibrous, connective, matrix macromolecules (e.g., collagens, fibronectins and proteoglycans) on and within the lungs, usually at sites of injury or infection. The excessive formation of fibrous tissue, resulting from the activation and proliferation of fibroblast cells, destructs normal lung structure and function. For instance, the accumulation of fibrous tissue thickens alveolar walls, obliterates air space, and causes epithelial injury or even alveolar collapse.
Patients suffering from pneumopathies (such as pneumonitis and pulmonary fibrosis) experience a varying degree of exertional dyspnea, and in late stages, orthopnea, cyanosis, and respiratory failure. Currently, there is no cure for radiation-induced pulmonary fibrosis. Median survival of radiation-induced pulmonary fibrosis is about 2-3 years.
Radiation-induced pneumopathy not only causes devastating effects on the quality of patient life, but sometimes can be even more life-threatening than the primary tumor or cancer. Consequently, the risk of radiation-induced pneumopathy, such as pulmonary fibrosis, has become a major dose-limiting factor and sometimes even prevents the use of radiation therapy.
There is a need for therapeutic formulations for prevention and treatment of radiation-induced lung injury and complications. As will be clear from the disclosures that follow, these and other benefits are provided by the subject invention.